Interactions between proteins play a pivotal role in almost all physiological and biochemical processes in living organisms. Proteins fulfill not only biocatalytic tasks (for example, as an enzyme), but rather are involved in a variety of biological processes. Selective inhibition of the physical interaction between peptide ligands and the corresponding protein receptors may have a significant influence on a variety of biological mechanisms in the cell.
In the state of the art there is therefore the need, in particular in the treatment of diseases, to develop molecules that inhibit specific protein-protein interactions in order to achieve biologically, i.e. medically, relevant technical effects.
Structural mimetics of diproline units are one example of such inhibitors. Based on its chemical structure, proline takes on a special role in comparison to other amino acids. Proline is the only secondary, proteinogenic amino acid that, after establishing a peptide bond, has no free NH proton for the formation of hydrogen bridge bonds. For this reason, polyproline sequences are unable to assume classic alpha helix or beta pleated sheet secondary structures. Due to these particular physical properties, polyproline amino acid sequences (e.g. proline-rich motifs (PRM)) are very well suited to initiate specific protein-protein interactions with receptors (e.g. proline-rich motifs binding domains (PBD)). By providing polyproline mimetics, a number of these interactions can be selectively inhibited.
A number of beta-turn peptidomimetics are known in the state of the art as modulators of protein-protein interactions. WO 2006/067091 A1 discloses a variety of peptides and peptidomimetics that prevent the homodimerization of MyD88 and the interaction between MyD88 and TIR. Beta-turn peptidomimetics are also known as modulators of protein-protein interactions between SH3 domains. WO 98/54208, for example,
discloses that beta-turn peptidomimetics, which have polyproline motifs and an alpha-helix structure, can interact with SH3 domains. Witter et al (Bioorg. Med. Chem. Lett. 8 (1998) 3137) and Vartak et al (Organic Lett. 2006, 8:5, 983) disclose a variety of beta-turn peptidomimetics that can be used as mimetics for a polyproline sequence.
Other chemical compounds that function as diproline mimetics are disclosed in WO 2008/040332 and in WO 2013/030111. For example, WO 2013/030111 discloses peptide compounds that have two adjacent diproline mimetics instead of four proline amino acids, whereby the diproline mimetics are flanked by peptide sequences. The peptides described therein exhibit good affinity to a VASP-EVH1 domain but, due to their specific peptide structure, they are expensive to produce. Due to the peptide structure and the presence of endogenous proteases, the peptide structures continue to be decomposed in vivo. A number of these compounds also exhibit sub-optimal cell permeability, which is quite detrimental to use as a medicament.
Even though the compounds disclosed therein can inhibit protein-protein interactions by selective binding to a receptor, there is still a need to provide further polyproline mimetics that have improved binding properties and exhibit the corresponding biological effects.